Methods and apparatus for pulsatile release of medicaments from a punctal plug

ABSTRACT

This invention discloses methods and apparatus for providing pulsatile release of active agents via a punctal plug inserted into a punctum. A tube is provided which may be inserted into a cavity of a punctal plug. One or more pulsatile delivery units are arranged in a generally linear fashion within the tube. The pulsatile delivery units include a core comprising the active agent and an encapsulation layer around the core.

RELATED APPLICATIONS

This application claims priority to Provisional Patent Application U.S.Ser. No. 61/238,470 which was filed on Aug. 31, 2009, the contents ofwhich are relied upon and incorporated by reference.

FIELD OF USE

This invention describes methods and apparatus for dispensing one ormore materials, such as a medicament, from a punctal plug reservoir and,in some embodiments, dispensing a drug component in a form conducive topulsatile release into a cavity of a punctal plug.

BACKGROUND

Medicaments frequently are administered to the eye for the treatment ofocular diseases and disorders. Conventional means for deliveringmedicaments to the eye involve topical application to the surface of theeye. The eye is uniquely suited to topical administration because, whenproperly constituted, topically applied medicaments can penetratethrough the cornea and rise to therapeutic concentration levels insidethe eye. Medicaments for ocular diseases and disorders may beadministered orally or by injection, but such administration routes aredisadvantageous in that, in oral administration, the active agent mayreach the eye in too low a concentration to have the desiredpharmacological effect and their use is complicated by significant,systemic side effects and injections pose the risk of infection.

The majority of ocular medicaments are currently delivered topicallyusing eye drops which, though effective for some applications, areinefficient. When a drop of liquid is added to the eye, it overfills theconjunctival sac, the pocket between the eye and the lids, causing asubstantial portion of the drop to be lost due to overflow of the lidmargin onto the cheek. In addition, a substantial portion of the dropthat remains on the ocular surface is drained into the lacrimal puncta,diluting the concentration of the drug.

Other methods allow for the eluding of a medicament over a period oftime. However, some medicaments are most efficacious when periodicallydelivered in a predetermined dosed amount. Accordingly, alternativemethods and devices for delivering medicaments to an ophthalmic area maybe beneficial.

SUMMARY

The present invention relates to devices for pulsatile administration ofa medicament via a punctal plug, and includes methods and apparatus forplacing a medicament in a punctal plug cavity wherein the medicament cansubsequently be delivered to a patient on a pulsatile basis with thepunctal plug inserted into a punctum.

According to the present invention, a tube is provided which may beinserted into a cavity of a punctal plug. One or more pulsatile deliveryunits are arranged in a generally linear fashion within the tube. Thepulsatile delivery units include a core comprising the active agent andan encapsulation layer around the core.

In some embodiments, a boundary layer is included between a firstpulsatile delivery unit and a second pulsatile delivery unit. Additionalembodiments include a boundary layer between a pulsatile delivery unitand an opening in the cavity of the punctal plug. By way of non-limitingexample, a boundary layer may include one or more of: a biodegradablemembrane; a semi-porous membrane or a mesh.

In another aspect, in some embodiments, an active agent-containingmaterial may include a poly(epsilon-caprolactone) and ethylene vinylacetate. The poly(epsilon-caprolactone) and ethylene vinyl acetate mayeach be present, for example, in an amount of about 50 weight percent.

In another aspect, in some embodiments, a first pulsatile delivery unitmay include a first active-agent containing material comprising arelatively low concentration of the active agent and a second pulsatiledelivery unit may include a second active-agent containing materialcomprising a relatively high concentration.

Other embodiments are included within the scope of the followingspecification and claims and accompanying drawings.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a punctal plug and method for deposition of pulsedoses into a punctal plug according to some embodiments of the presentinvention.

FIG. 2 illustrates apparatus for punctal plug deposition according tosome embodiments of the present invention.

FIG. 3 illustrates a block graph of an amount of medicament deliveredvia pulsatile delivery over a period of time.

FIG. 4 illustrates a pulsatile medicament delivery package.

FIGS. 5A-5C illustrate a punctal plug with a pulsatile release insert.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes apparatus and methods for forming punctalplugs that may be used to deliver active agents to one or both of thenasolacrimal ducts and to the tear fluid of the eye, wherein thedelivery of the active agent takes place in a pulsatile pattern. Alocation for dissemination of an active agent is positioned to releasethe active agent into tear fluid and preferably with minimal releaseinto the nasolacrimal duct. The pulsatile pattern is accomplished bylinearly aligning water soluble encapsulated beads or other pulsatiledelivery unit in a carrier, such as a tube and regulating exposure ofeach pulsatile delivery unit to an aqueous solution, such as tear fluid.As a first pulsatile delivery unit is exposed to the aqueous solutionand dissolved, a medicament encapsulated within the pulsatile deliveryunit is then released into the nasolacrimal duct. Dissolving of a firstpulsatile delivery unit and consequent release of a first dose ofmedicament then exposes a second pulsatile delivery unit to the aqueoussolution. The pattern repeats itself as the linearly aligned pulsatiledelivery units are dissolved and expose a next unit to the aqueoussolution.

Some embodiments include apparatus and methods for forming a punctalplug comprising, consisting essentially of, and consisting of: a punctalplug body having a first end and a second end; a surface extendingbetween the two ends; a reservoir contained within the punctal plug bodywherein the reservoir comprises, consists essentially of and consists ofan active agent-containing material and an active agent, wherein theactive agent is linearly present in a pulsatile dosing bead. The punctalplug may additionally comprise a defined area, such as an opening in thepunctal plug, which is more conducive to elution or other disseminationof the active agent from the punctal plug cavity to an area proximate tothe punctal plug. Some preferred embodiments include an area conduciveto dissemination of the active agent comprising an opening with adiameter which is smaller than a diameter of the cavity containing theactive ingredient.

The present invention additionally provides devices, and methods fortheir use and manufacture, that can be used to deliver active agentsinto a cavity in a punctal plug in a controlled manner.

It has been known to fill a cavity in a punctal plug via insertion of arod, or other rigid or semi rigid article. The rod can include apharmaceutical or other medicament. However, previously knownadministration relied upon an active agent eluding from the plug.According to the present invention, a linear progression of pulses of anactive agent is delivered.

Definitions:

As used herein, the term “active agent” refers to an agent capable oftreating, inhibiting, or preventing a disorder or a disease. Exemplaryactive agents include, without limitation, pharmaceuticals andnutraceuticals. Preferred active agents are capable of treating,inhibiting, or preventing a disorder or a disease of one or more of theeye, nose and throat.

As used herein, the term “punctal plug” refers to a device of a size andshape suitable for insertion into the inferior or superior lacrimalcanaliculus of the eye through, respectively, the inferior or superiorlacrimal punctum.

As used herein, the term “opening” refers to an opening in the punctalplug body of a device of the invention of a size and shape through whichthe active agent can pass. Preferably, only the active agent can passthrough the opening. The opening may be covered with a membrane, mesh,grid 106 or it may be uncovered. The membrane, mesh, or grid may be oneor more of porous, semi-porous, permeable, semi-permeable, andbiodegradable.

Referring now to FIG. 1, at 1A a medicament tube 101 is illustrated withan opening 102 which fluidly communicates with a cavity 105 formed inthe medicament tube 101 body. At 1B, a dispenser tip 103 is positionedproximate to the opening 102 and dispenses a pulsatile delivery unit 104through the opening 102 and into the cavity 105. Examples of activeagents that can be included in the pulsatile delivery unit 104 includeone or more of: bimatoprost; bimatoprost with an ethyleneoxynalacetate.At 1C, in some embodiments, the cavity 105 may also be filled by thedispenser tip 103 with a boundary layer 106 or membrane. Preferredembodiments include a boundary layer 106 that is soluble in tear fluid.A thickness of a boundary layer 106 and a time to dissolve a boundarylayer when it is exposed to an aqueous solution can be correlated inorder to design in a predetermined amount of time for an aqueoussolution, such as tear fluid to access linearly aligned pulsatiledelivery units. Accordingly, the boundary layer thickness and physicalcharacteristics can be adjusted to control a time period between pulsesof medicaments being delivered to an eye, or nasolacrimal duct.

At 1D, in some embodiments the tube 105 can contain multiple pulsatiledelivery units 104 comprising a sphere of encapsulated aqueous solutionor oil. Other embodiments include an encapsulated compound including anactive agent and an excipient. Each pulsatile delivery unit may includedoses of an active agent or medicament, of between, by way ofnon-limiting example, 10 (ten) picoliters and 100,000 (ten thousand)picoliters. The pulsatile delivery unit 104 may also include one or moreexcipients.

The cavity may be any size and/or shape that a punctal plug design maysupport. In some embodiments, the volume of the cavity 105 will be aboutbetween 10 and 100 nanoliters. Some specific embodiments include acavity volume of about between 40 nanoliters and 50 nanoliters. Anopening 102 to a cavity into which a dispenser tip may be inserted, maybe, for example, include a diameter of between about 0.1 mm to 0.4 mmand a cavity 105 may include a depth of between about 0.5 mm to about2.0 mm. In some preferred embodiments, the opening 102 will be about 0.2mm and the depth of the cavity will be about 1.5 mm. Additionalpreferred aspects of embodiments can include a design with a 0.385diameter and 1.5 mm length with a cavity volume of 175nL.

The active agent may be dispersed throughout the active agent-containingpulsatile delivery unit 104 or dissolved within the pulsatile deliveryunit 104. Alternatively, the active agent may be contained ininclusions, particulates, droplets, or micro-encapsulated within thepulsatile delivery unit 104. Still as another alternative, the activeagent may be covalently bonded to the pulsatile delivery unit 104 andreleased by hydrolysis, enzymatic degradation and the like. Yet asanother alternative, the active agent may be in a reservoir within thepulsatile delivery unit 104.

At 1F pulsatile delivery units 104 may be separated by one or moremembrane layers 106. The membrane layers 106 may include variousproperties. Embodiments can therefore include membrane layers comprisingone or more of: biodegradable semi-permeable membranes,non-biodegradable semi-permeable membranes, pores and combinationsthereof.

Referring now to FIG. 2, an example of some embodiments of the presentinvention which include a punctal plug active agent pump 200 fordepositing the pulsatile delivery unit 104 into a cavity 105 of amedicament tube 101 (illustrated in FIG. 1). Generally, the pump 200includes a reservoir for containing pulsatile delivery units 104, suchas a cartridge 201, mounted in a pump body 207 and attached to providefluid communication to a dispenser tip 203. The cartridge 201 caninclude, for example, a modified removable syringe with a largedispensing opening.

The cartridge 201 can be formed from a polycarbonate, stainless steel orother rigid or semi-rigid material. In some preferred embodiments, thecartridge is formed from a material that can be sterilized and alsowithstand heating during the deposition process. Additionally, in someembodiments, the cartridge 201 will have an end proximate to thedispenser tip 203 and an end distal to the dispenser tip, wherein theend proximate to the dispenser tip can include a lure lock mechanism forsecuring the cartridge 201 to a dispenser body 202. Other locking orfastening mechanisms may also be used to secure the cartridge 201 in aposition proximate to and in fluid communication with the dispenser tip203. Some embodiments may therefore include designs of a polycarbonateor stainless steel syringe.

Some embodiments can include a positive pressure pump with a computercontrolled valve, which control starts and stops dispensing of pulsatiledelivery units 104. A computer controlled valve provides active valvingto control flow characteristics. In some embodiments, the presentinvention may dispense very small volumes of an active agent-containingin a pulsatile delivery unit 104. Some embodiments can include volumesof 50 picoliters or less and in some preferred embodiments, volumes ofbetween 20 picoliters to 60 picoliters.

Some preferred embodiments will include one or more temperature controldevices 204-206 for cooling or heating the pulsatile delivery unit 104while it is in one or more of: a) the cartridge 201; b) the dispenserbody 202; and c) the dispenser tip 203. The temperature control devices204-206 can include, for example, one or more of: a thermoelectricdevice, electrically resistive elements and temperature controlled fluidpaths. As illustrated, in some embodiments, a temperature control device205 may be located along side the cartridge 201 and allow the materialwith an active ingredient 104 to be kept at an elevated temperaturewhile in the cartridge 201. Some embodiments can also include atemperature control device 204 in or proximate to the pump body 207.Some embodiments may also include temperature requirements that may beadjusted according to material properties excipients to be deposited.

In another aspect, some embodiments of the present invention include atemperature probe 206. The temperature probe can include a transducerfor providing a digital or analog output indicating a temperature of adesignated portion of the punctal plug active agent pump 200.Embodiments can include an electronic feedback circuit (not shown),which allows control of an amount of heat applied to the activeingredient 104. In some embodiments, the feedback constitutes a closedloop feedback design.

Additionally, in some embodiments, an amount of heat applied to thepulsatile delivery unit 104 can be used to control a formability factorof a material containing an active ingredient 104. Typically, a higheramount of heat applied will lower the rigidity of the pulsatile deliveryunit 104 and allow for less pressure to be applied to move the pulsatiledelivery unit 104 through the punctal plug active agent pump 200. By wayof example, a pulsatile delivery unit 104 can be dispensed through thedispenser tip 203 at a temperature of between 40° C. and 80° C. and insome preferred embodiments at a temperature of between 60° C. and 70° C.In some particular embodiments, a punctal plug 101 into which thematerial containing the active pulsatile delivery unit 104 is dispensedis also heated to a temperature of between 40° C. and 80° C. In someembodiments, the application of heat to the punctal plug 101 can provideadditionally elasticity to the plug during the deposition allowing thecavity 105 to expand and more easily accept the material containing anactive ingredient 104. In various embodiments, a preferred temperaturemay be based upon one or more of: an active ingredient used; anexcipient included in the material containing an active ingredient 104;and a material used to encapsulate a pulsatile delivery unit 104.

Referring now to FIG. 3, a graph illustrates a generalized releasepattern in pulsatile release. Over time 302, pulses in medicamentrelease 303 are experienced. A time period of lower medicament releaseor essentially no medicament release 302 are experienced in between thepulses 302.

In some embodiments, a boundary layer 106 can be included within amedicament tube 101 in order to create a time period of lower medicamentrelease or essentially no medicament release 302.

According to some embodiments of the present invention the active agentis released from the medicament tube 101 in a consistent pulsatilepattern, meaning in generally equal volume pulses and of generally equalconcentration over a period of time by using an active agent-containingpulsatile delivery unit 104 in which the agent is present in a similarsize pulse (as dependent upon a similar size pulsatile delivery unit).The pulses 303 may also be of similar concentration in each of thepulsatile delivery unit 104. Additional embodiments include a devicethat exhibits a “burst” or immediate release upon insertion of an amountof active agent that is greater than the average release of otherpulsatile delivery units 104. Still other embodiments include varyingone or more of: the size of a pulsatile delivery unit 104; aconcentration of medicament within the pulsatile delivery unit 104, thespacing of the pulsatile delivery units 104.

Some exemplary embodiments can also include pulsatile delivery unit 102containing a material with a mix of excipients and active agents.Pre-mixing apparatus and processes may include twin-screw compounding,chaotic mixing, solvent mixing, or spray drying, or other mixingmechanisms. An exemplary compound can include: 25% bimatoprost as anactive agent; 37.5% ethylene vinyl acetate, EVA as a first excipient and37.5% polycaprolactone, PCL as a second excipient.

The pre-mixed material can be loaded into the heated or non-heatedsyringe 200 as pellets. Pellets are not a requirement; the active agentcan be in the form of one or more of: a powder, fluff and other mediums.Additionally, in some embodiments, such as those in which it is desiredto avoid multiple thermal cycle exposure of an active agent and/or tominimize air bubbles, the heated syringe may be directly attached to themicro-compounder so that the pre-mixed material is directly suppliedinto a nano-dosing dispensing system, such as those described above,without having to cool it to room temperature or lower. As such, in someembodiments the material containing an active agent may be supplied tothe nano-dispensing system in a melt form.

In another aspect of the present invention, a gradient of concentrationof active agent released may be controlled by placing pulsatile deliveryunits 102 with more active agent at one location in a linear progressionand a material containing an active agent 104 in another concentrationat another relative linear position. Alternatively, the matrix may behave a gradient, meaning that one section of the pulsatile delivery unit104 has a first concentration and the concentration abruptly changes toa second, different concentration in an adjacent section of the matrix.The diffusivity for the active agent may also be spatially controlled byvarying one or more of the chemical composition, porosity, andcrystallinity of the active agent-containing pulsatile delivery unit104.

Referring now to FIG. 4, a medicament tube 401 is illustrated withmultiple pulsatile delivery units 403 arranged in a generally linearfashion. A boundary material 402 is also viewable in a cutaway of themedicament tube 401. The linear arrangement enables on pulsatiledelivery unit at a time to be accessed by body fluids and dispersed intothe eye or nasolacrimal duct.

As illustrated, the pulsatile delivery units 403 include anencapsulation layer 404 and a medicament core 405. Encapsulation may beaccomplished via any known method including, for example PrecisionParticle Fabrication (PPF) technology for the production of monodisperseliquid-filled microcapsules containing an oil or aqueous core ordouble-walled microspheres. Examples of encapsulated pulsatile deliveryunits can include, monodisperse polymeric microcapsules encapsulating anoil or aqueous core in or double-walled (polymer core/polymer shell)microcapsules. Molecules can be localized to the core or shell phase toenable advanced controlled release profiles, including the pulsatileactive agent delivery.

Referring now to FIG. 5, at 5A, punctal plug devices 501 formedaccording to the present invention may contain a reservoir or cavity 505within the punctal plug body 506, with an opening 502 accessing thecavity 505. At 5B, one or more medicament tube 503 containing one ormore pulsatile release units 504 is inserted into the cavity 505. Thepulsatile release units preferably contain at least one active agent. At5C the medicament tube is fully inserted into the punctal plug and insome embodiments includes a seal 507 that remains intact until utilizedthe punctal plug device 501 in placed a patient.

The active agent-containing material useful in the devices of theinvention is any material that is capable of containing the activeagent, does not alter the chemical characteristics of the active agent,and does not significantly chemically degrade or physically dissolvewhen placed in contact with ocular fluids. Preferably, the activeagent-containing material is non-biodegradable, meaning that it does notdegrade to a substantial degree upon exposure to biologically activesubstances typically present in mammals. Additionally, the activeagent-containing material is capable of releasing the active agent byone or more of diffusion, degradation, or hydrolyzation. Preferably, theactive agent-containing material is a polymeric material, meaning thatit is a material made of one or more types of polymers.

When the active agent-containing material is combined with the activeagent, the material may also contain one or more materials that areinsoluble in water and non-biodegradable, but from which the activeagent can diffuse. For example, if the active agent-containing materialis a polymeric material, the material may be composed of one or morepolymers that are insoluble in water and non-biodegradable.

Suitable polymeric materials for the active agent-containing materialinclude, without limitation, hydrophobic and hydrophilic absorbable andnon-absorbable polymers. Suitable hydrophobic, non-absorbable polymersinclude, without limitation, ethylene vinyl alcohol (“EVA”), fluorinatedpolymers including without limitation, polytetrafluoroethylene (“PTFE”)and polyvinylidene fluoride (“PVDF”), polypropylene, polyethylene,polyisobutylene, nylon, polyurethanes, polyacrylates and methacrylates,polyvinyl palmitate, polyvinyl stearates, polyvinyl myristate,cyanoacrylates, epoxies, silicones, copolymers thereof with hydrophobicor hydrophilic monomers, and blends thereof with hydrophilic orhydrophobic polymers and excipients.

Hydrophilic, non-absorbable polymers useful in the invention include,without limitation, cross-linked poly(ethylene glycol), poly(ethyleneoxide), poly(propylene glycol), poly(vinyl alcohol), poly(hydroxyethylacrylate or methacrylate), poly(vinylpyrrolidone), polyacrylic acid,poly(ethyloxazoline), and poly(dimethyl acrylamide), copolymers thereofwith hydrophobic or hydrophilic monomers, and blends thereof withhydrophilic or hydrophobic polymers and excipients.

Hydrophobic, absorbable polymers that may be used include, withoutlimitation, aliphatic polyesters, polyesters derived from fatty acids,poly(amino acids), poly(ether-esters), poly(ester amides), polyalkyleneoxalates, polyamides, poly(iminocarbonates), polycarbonates,polyorthoesteres, polyoxaesters, polyamidoesters, polyoxaesterscontaining amine groups, phosphoesters, poly)anhydrides), polypropylenefumarates, polyphosphazenes, and blends thereof. Examples of usefulhydrophilic, absorbable polymers include, without limitation,polysaccharides and carbohydrates including, without limitation,crosslinked alginate, hyaluronic acid, dextran, pectin, hydroxyethylcellulose, hydroxy propyl cellulose, gellan gum, guar gum, keratinsulfate, chondroitin sulfate, dermatan sulfate, proteins including,without limitation, collagen, gelatin, fibrin, albumin and ovalbumin,and phospholipids including, without limitation, phosphoryl cholinederivatives and polysulfobetains.

More preferably, the active agent-containing material is a polymericmaterial that is polycaprolactone. Still more preferably, the materialis poly(epsilon-caprolactone), and ethylene vinyl acetate of molecularweights between about 10,000 and 80,0000. About 0 to about 100 weightpercent polycaprolactone and about 100 to about 0 weight percent of theethylene vinyl acetate are used based on the total weight of thepolymeric material and, preferably, about 50% each of polycaprolactoneand ethylene vinyl acetate is used.

The polymeric material used is preferably greater than about 99% pureand the active agents are preferably greater than about 97% pure. One ofordinary skill in the art will recognize that in compounding, theconditions under which compounding is carried out will need to take intoaccount the characteristics of the active agent to ensure that theactive agents do not become degraded by the process. Thepolycaprolactone and ethylene vinyl acetate preferably are combined withthe desired active agent or agents, micro-compounded, and then extruded.

In a preferred embodiment, the active agent-containing material is apolymeric material that is combined with at least one active agent toform a highly viscous material, such as, for example with a viscosity ofbetween 500,000 cP and 4,000,000 cP. Preferably the viscosity of theactive agent containing material can be decreased by heating the activeagent containing material while it is contained in, or passing through adispensing pump according to the present invention.

In some embodiments, the punctal plug body is preferably impermeable tothe active agent, meaning only an insubstantial amount of active agentcan pass there through, and the punctal plug body has at least oneopening through which the active agent is released. The opening may havea membrane or permeable material covering through which the active agentmay pass in therapeutic amounts.

CONCLUSION

The present invention, as described above and as further defined by theclaims below, provides methods of processing punctal plugs and apparatusfor implementing such methods, as well as punctal plugs formed thereby.

1. A pulsatile delivery device of an active agent, the devicecomprising: a tube inserted into a cavity of a punctal plug; and one ormore pulsatile delivery units arranged in a generally linear fashionwithin the tube, wherein two or more pulsatile delivery units comprise acore comprising the active agent and an encapsulation layer around thecore.
 2. The pulsatile delivery device of claim 1 wherein the one ormore pulsatile delivery units comprise water soluble encapsulated beads.3. The pulsatile delivery device of claim 2 wherein the generally lineararrangement of the pulsatile delivery units limits exposure of pulsatiledelivery units to tear fluid to one pulsatile delivery unit at a time.4. The pulsatile delivery device of claim 2 further comprising aboundary layer between a first pulsatile delivery unit and a secondpulsatile delivery unit.
 5. The pulsatile delivery device of claim 1further comprising a boundary layer between a pulsatile delivery unitand an opening in the cavity of the punctal plug.
 6. The pulsatiledelivery device of claim 5 wherein the boundary layer comprises abiodegradable membrane.
 7. The pulsatile delivery device of claim 5wherein the boundary layer comprises a semi-porous membrane.
 8. Thepulsatile delivery device of claim 5 wherein the boundary layercomprises a mesh.
 9. The pulsatile delivery device of claim 2, whereinthe active agent-containing material comprisespoly(epsilon-caprolactone) and ethylene vinyl acetate.
 10. The pulsatiledelivery device of claim 9, wherein the poly(epsilon-caprolactone) andethylene vinyl acetate are each present in an amount of about 50 weightpercent.
 11. The pulsatile delivery device of claim 2, wherein the tubecomprises a first pulsatile delivery unit comprising a firstactive-agent containing material comprising a relatively lowconcentration of the active agent and a second pulsatile delivery unitcomprising a second active-agent containing material comprising arelatively high concentration.
 12. The pulsatile delivery device ofclaim 1 wherein the core comprises an active agent-containing materialand a phase separated inclusion.
 13. The pulsatile delivery device ofclaim 1 wherein the core comprises an active agent-containing materialand a destabilizing inclusion.
 14. The pulsatile delivery device ofclaim 1 wherein the core comprises an active agent-containing materialand a stabilizing inclusion.
 15. The pulsatile delivery device of claim1 wherein the punctal plug additionally comprises a punctal plug bodyand a cavity within the punctal plug body.
 16. The pulsatile deliverydevice of claim 15 wherein the punctal plug additionally comprises anaccess opening to the cavity from a position external to the body whenthe plug is inserted into a punctum.
 17. The pulsatile delivery deviceof claim 15 wherein the punctal plug additionally comprises a sealacross the opening to the cavity, blocking access to the cavity from aposition external to the body when the plug is stored outside a punctum.